Signaling pathways modulating HIV-1 induced injury in CNS The central goals and objective of this competing renewal program project remain on the utilization of a multidisciplinary approach to decipher the molecular signaling events that mediate development of brain cell injury upon HIV-1 infection. HIV-1 infection of brain microglia and perivascular macrophages as well as astrocytes leads to the secretion of viral and cellular factors causing chronic inflammation, triggering signal transduction and inducing oxidative stress. All these events can impact on the overall replication of HIV-1 in infected cells, and via a complicated chain of cytoplasmic reactions, transmit signals to the nuclei of the uninfected cells such as neurons, hence leading to gene-directed neuronal death and apoptosis. In this research program, we will employ a number of molecular, genetic, virological, and neuropathological approaches to launch a truly multidisciplinary effort for understanding signaling events that are involved in the neuropathogensis of HIV-1 infection in the brain. Thus, the central theme of this program rests on studying HIV-1-CNS interaction by focusing our attention on the interplay between viral protein such as Tat and Vpr, and host signaling pathways that control host homeostasis. In Project #1, we will aim to investigate the role of Tat in inducing neuronal cell dysfunction by focusing our attention on Rho GTPases, one of the most influential biological pathways in neuronal cell differentiation and survival. In Project #2, we will test the hypothesis that degeneration of neuronal processes is caused by TNFa-induced interaction between phosphorylated IRS-1, a key component of IGF signaling pathway, and integrins that leads to the retraction of neuronal processes. Finally, in Project #3, we will investigate the impact of HIV-1 infection on oxidative stress factors such as hypoxia inducible factor 1 (HIF-1) and the cooperativity of HIF-1 and Vpr in the regulation of viral gene expression and replication in cells supporting HIV-1 replication in the brain. The Neuropathological and Cell Culture Core will function as a central service facility for receiving, evaluating, and distributing clinical samples and preparing specific cell cultures and viral stocks to each project. The Administrative Core will handle all administrative activities related to the project such as grant management, purchasing, shipment, progress reports, protocols, etc.